Journal Club; April 12, 2012, R Minhas
Parsons et al. A randomized trial of Tenecteplase vs. Alteplase for Acute Ischemic Stroke
Background
The only approved thrombolytic agent for acute ischemic stroke is IV alteplase (tPA).
Tenecteplase (TNK), a genetically engineered mutant tissue plasminogen activator
(already used for MI) is an alternative thrombolytic agent.
Theoretical advantages of TNK: Higher fibrin specificity, reduced binding affinity to
plasminogen activator inhibitor (PAI-1), a longer half-life, and a rapid single bolus
infusion.
Rationale
Objective
Trial Design
tPA leads to incomplete and delayed reperfusion in many patients.
TNK has some pharmacokinetic advantages over tPA
Dose ranging study of TNK in stroke tx showed that 0.4 mg/kg dose was associated
with excess intracranial hemorrhage.
Nonrandomized pilot trial showed that TNK dose of 0.1 mg/kg had superior outcomes
on imaging and clinical improvement vs. tPA dose of 0.9 mg/kg
To compare standard dose of tPA with 2 different doses of TNK in patients with acute
ischemic stroke.
1° hypothesis: TNK is superior to tPA with respect to one or both coprimary outcomes
(% reperfusion and changes in the NIHSS score at 24 hrs)
Phase 2 B trial, randomized, open, blinded trial. Central block randomization by
means of central telephone service in blocks of 15 patients.
Trial conducted from 2008-2011, 3 large stroke centers in Australia
CT perfusion and angiographic imaging used to select patients who would be the
most likely to benefit from early reperfusion (i.e. patients with large-vessel occlusion
and a perfusion lesion at least 20% greater than the infarct core on CT perfusion
imaging).
The study asked a
clearly focused
question.
Randomized
Treating clinician aware
of treatment
assignments
Allocation concealment
performed
Assessors of imaging outcomes and trained observers unaware of tx assignment and
clinical information.
Patient
Population
Eligibility
With acute ischemic stroke selected based on CT perfusion and angiographic imaging.
2768 patients screened for participation. 75 underwent randomization (See page 4).
Exclusion Criteria? Lots
of pts excluded
Specific additional advanced imaging criteria: Large # of patients who were eligible
for thrombolysis on the basis of standard clinical and noncontrast CT were excluded.
Differences b/w groups
with respect to baseline
characteristics
Significant differences between groups: tPA group had fewer people with diabetes,
fewer smokers and a lower mean blood glucose level.
Small sample size
Inclusion Criteria:
 First ever hemispheric ischemic stroke who were > 18 years of age
 NIHSS > 4 (National Institutes of Health Stroke Scale)
 mRS < 2 (modified Rankin scale)
Exclusion Criteria:
 Standard contraindications to tPA, Specific imaging exclusion criteria
Specific Selection Criteria:
A perfusion lesion of at least 20% > than the infarct core on CT perfusion imaging at
baseline and an associated vessel occlusion on CT angiography.
tPA group seemed to
have more proximal
middle cerebral artery
occlusions strokes vs.
TNK group.
Journal Club; April 12, 2012, R Minhas
Intervention Before randomization: CT perfusion and angiographic imaging
Time of administration of thrombolytic: within 6 hours after onset of stroke
MRI @ 24 hours after treatment and 90 days for assessment of imaging outcomes
Outcomes
75 patients underwent randomization: 3 groups of 25 each received tPA (0.9 mg/kg),
TNK (0.1 mg/kg) and TNK (0.25 mg/kg)
1. 1° imaging efficacy outcome: Reperfusion at 24 hr
2. 1° clinical efficacy outcome: Improvement in NIHSS score b/w baseline and 24 hr
3. 2° imaging efficacy outcome: Infarct growth at 24 hr and at 90 days, complete
recanalization at 24 hr, complete or partial recanalization at 24 hr
4. 2° imaging safety outcome: Large parenchymal hematoma, any parenchymal
hematoma, symptomatic intracranial hematoma
5. 2° clinical efficacy outcome: major neurologic improvement at 24 hr (reduction
of >8 in NIHSS score), excellent recovery (mRS= 0 or 1) at 90 days, excellent or
good recovery (mRS= 0 to 2)at 90 days
6. 2° clinical safety outcome: poor outcome (mRS 5 or 6) at 90 days, death
7. Post hoc secondary imaging outcome: volume reperfusion at 24 hr, mismatch
salvage at 24 hr, mismatch salvage at 90 days
6 hours?
Trial end points
modified before the
end of the trial.
1° outcome Reperfusion
changed from absolute
volume change to
proportional change.
Infarct growth replaced
“mismatch salvage”
(volume of penumbra
that did not grow into
infarct) as 2° outcome.
Post hoc analysis of
original end points
performed
Statistics
Alpha level = 0.025 prespecified for 2 primary end points
Sample size calculated on the basis of pilot study, power set at 80% and an
assumption of superiority with respect to one of the two coprimary outcomes.
Testing of 1⁰ hypotheses: Unadjusted student’s t-test of means.
Analysis repeated after adjustment for potential confounding baseline variables.
Testing of 2° outcomes with a nonparametric distribution: Wilcoxon rank-sum test.
Comparison of categorical variables: Chi-square test of proportions or Fisher’s exact
test
Results –
Efficacy
Mean (+ SD) NIHSS score at baseline: 14.4+2.6
Time to treatment: 2.9+0.8 hrs
Endpoint
Alteplase
Tenecteplase
P Value
Reperfusion at 24 hours (%, SD)
55.4 ±
38.7
79.3 ± 38.7
.004
Improvement in NIHSS score from baseline to
24 hours (points, SD)
3.0 ± 6.3
8.0 ± 5.5
< .001
Beneficial for 2° outcomes: Infarct growth was ↓, a higher proportion of patients had
an excellent or good recovery (mRS of 0-2 at 90 days (72% vs. 44%, P=0.02)
Higher dose of TNK superior to lower dose and tPA for all efficacy outcomes.
Excellent recovery (no clinically significant disability) in 72% vs. 40% in tPA (P=0.02)
Lower dose of TNK vs. tPA: Greater clinical improvement at 24 hrs with lower dose
(P=0.04), other efficacy outcomes were equivalent
Pooled TNK (50
patients) compared to
tPA alone (25 patients),
appropriate to
compare?
Journal Club; April 12, 2012, R Minhas
Results –
Safety
No significant between group differences in intracranial bleeding or other serious
adverse events but more patients had parenchymal hematoma in tPA grpup (4% vs.
16%)
Authors’
conclusion
TNK associated with significantly better reperfusion and clinical outcomes vs. tPA in
patients with stroke selected on the basis of CT perfusion imaging.
Bottom Line
The results do favor TNK but it is too early to draw any definitive conclusions.
Application
to Clinical
Practice
Results cannot be extrapolated to majority of patients who are eligible for
thrombolysis.
6 hours of window to administer thrombolytic (only 3 patients were treated after 4.5
hrs)? Previous studies have shown that 6 hour window is not effective or safe.
Phase 3 trial should be conducted to determine whether same results can be
established in a broader population of patients
Appendix:
NIHSS (National Institute of Health Stroke Scale): 42 point scale that quantifies neurologic deficits in 11
categories, with higher scores indicating more severe deficits.
mRS (modified Rankin Scale (ranges from 0-6)
0: no symptoms, 1: minor but no clinically significant disability, 2: slight disability, 6: death
Recovery assessed with mRS:
Excellent recovery: Score of 0 or 1
Excellent or good recovery: 0-2
Poor outcome: 5 or 6
Mismatch salvage: Volume of mismatch on CT perfusion imaging at baseline that did not progress to
infarction
Symptomatic intracranial hematoma: Large parenchymal hematoma and clinical worsening (an increase
in the NIHSS score of > 4)
CT angiographic criterion: Presence of intracranial occlusion in anterior, cerebral, middle cerebral or
posterior cerebral artery. Excluded patients with internal carotid artery and vertebrobasilar occlusions
CT perfusion criterion: Hemispheric perfusion lesion on transit-time maps that was at least 20% >
infarct-core lesion, with a volume of at least 20 mL. The infarct-core lesion on CT perfusion maps of
cerebral blood volume had to be < 1/3 rd the territory of the middle cerebral artery or < ½ the territory
of the anterior cerebral or posterior cerebral artery.
References:
1. Parsons et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N
Engl J Med 2012;366: 1099-107.
2. Jeffrey S. Tenecteplase vs. alteplase for stroke. Medscape [cited Apr 10 2012]. Available from:
http://www.medscape.com/viewarticle/760809
Journal Club; April 12, 2012, R Minhas
Journal Club; April 12, 2012, R Minhas
Journal Club; April 12, 2012, R Minhas